Modulation of m6A RNA modification by DAP3 in cancer cells

• 成果类型: Article
• 署名作者: Han, Jian; Song, Yangyang; Xie, Jinghe; Tano, Vincent; Shen, Haoqing; Gan, Wei Liang; Ng, Larry; Ng, Bryan Yik Loong; Ng, Vanessa Hui En; Sui, Xiaohui; Tang, Sze Jing; Chen, Leilei
• 署名单位: National University of Singapore; National University of Singapore
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12064
• DOI: 10.1073/pnas.2404509121
• 发表日期: 2024-10-01
• 关键词: s-adenosylmethionine; m(6)a methyltransferase; mettl16; GROWTH; progression; DISCOVERY; apoptosis; gene

摘要

N6- methyladenosine (m6A) RNA methylation is a prevalent RNA modification that significantly impacts RNA metabolism and cancer development. Maintaining the global m6A levels in cancer cells relies on RNA accessibility to methyltransferases and the availability of the methyl donor S- adenosylmethionine (SAM). Here, we reveal that death associated protein 3 (DAP3) plays a crucial role in preserving m6A levels through two distinct mechanisms. First, although DAP3 is not a component of the m6A writer complex, it directly binds to m6A target regions, thereby facilitating METTL3 binding. Second, DAP3 promotes MAT2A's last intron splicing, increasing MAT2A protein, cellular SAM, and m6A levels. Silencing DAP3 hinders tumorigenesis, which can be rescued by MAT2A overexpression. This evidence suggests DAP3's role in tumorigenesis, partly through m6A regulation. Our findings unveil DAP3's complex role as an RNA- binding protein and tumor promoter, impacting RNA processing, splicing, and m6A modification in cancer transcriptomes.